Saccharomyces cerevisiae (S. cerevisiae) is the primary microorganism that is currently used for biofuel production from sugars derived from plant materials. However, S. cerevisiae cannot ferment xylose, the second most abundant sugar in cellulosic hydrolyzates. Therefore, there is great interest in developing efficient xylose-fermenting strains of S. cerevisiae. 
Three major approaches have been taken to attempt to metabolically engineer xylose-fermenting strains of S. cerevisiae. First, attempts have been made to introduce into S. cerevisiae heterologous genes for assimilating xylose. Genes for assimilating xylose are found in certain species of yeast which naturally have the ability to ferment xylose, such as Schejfersomyces stipitis (S. stipitis), also known as Pichia stipitis (P. stipitis). In S. stipitis, xylose is reduced to xylitol by NADPH or NADH-linked xylose reductase (XR) (S. stipitis gene XYL1 (“SsXYL1”) and xylitol is subsequently oxidized to xylulose by NAD+-linked xylitol dehydrogenase (XDH) (S. stipitis gene XYL2 (“SsXYL2”). Xylulokinase (XK) (S. stipitis gene XYL3 (“SsXYL3”) phosphorylates xylulose into xylulose-5-phosphate which can be metabolized through the pentose phosphate pathway (PPP). It has been hypothesized that the cofactor difference between XR and XDH can lead to cellular redox imbalance, possibly reducing xylose consumption rate as well as triggering oxidative metabolism in response to xylose. Much research has been performed to optimize the cofactor usage of XR and XDH by protein engineering, but to date, the improvement in xylose metabolism has been marginal. Many efforts in finding the best set of XR and XDH are still continuing.
Second, it has been demonstrated that introduction of xylose isomerase (XI) from bacteria and anaerobic fungi (e.g. the xylA gene) into yeast can confer xylose fermentation under anaerobic conditions. This XI pathway is one step isomerization, which has no substrate loss and no cofactor requirement. However, it is not as energetically favorable as the XR/XDH pathway, resulting in slow conversion of xylose.
Third, internal limitations of S. cerevisiae in metabolizing xylose have been identified which are present in S. cerevisiae, regardless of the type of xylose-assimilating pathway used. The introduction of xylose-specific transporters and overexpression of some genes in the PPP have improved xylose metabolism by engineered S. cerevisiae. 
The existence of an endogenous metabolic pathway in S. cerevisiae for assimilation of xylose has also been suggested. Batt et al. demonstrated that wild type S. cerevisiae could metabolize very limited amounts of xylose, although it could not grow on xylose as a sole carbon source (Batt et al., Biotechnol. Bioeng., 28:549-553 (1986)). Through testing phenotypes of deletion mutants of putative endogenous XRs within S. cerevisiae, Traff et al. proposed that the S. cerevisiae gene GRE3 (“ScGRE3”) (an aldose reductase (AR)) might encode an enzyme having xylose reductase activity (Traff et al. Yeast, 19: 1233-1241, (2002)). Additionally, it has been reported that an engineered S. cerevisiae strain overexpressing ScGRE3 with S. cerevisiae XYL2 (ScXYL2) or S. stipitis XYL2 (SsXYL2) grew on xylose and produced xylitol (Traff-Bjerre et al., Yeast, 21: 141-150, (2004); Toivari et al, Appl. Environ. Microbiol, 70: 3681-3686, (2004)). However, ethanol production by the engineered S. cerevisiae strains with ScGRE3 overexpression was not significant. Aldose reductase encoded by ScGRE3 can reduce xylose into xylitol. However, ScGRE3 AR uses only NADPH as a cofactor, unlike SsXYL1 XR, which can use either NADPH or NADH. Therefore, it has been hypothesized and experiments have suggested that overexpression of ScGRE3, rather than SsXYL1, is detrimental for xylose fermentation by S. cerevisiae, due to redox imbalance. Traff-Bjerre et al. reported that an S. cerevisiae strain overexpressing ScGRE3, SsXYL2, and the S. cerevisiae XK gene XKS1 (“ScXKS1”) exhibited a 5 times slower xylose consumption rate as well as a lower ethanol yield, as compared to a control strain overexpressing SsXYL1, SsXYL2, and ScXKS1 (Traff-Bjerre et al. Yeast, 21: 141-150, (2004)). Toivari et al. showed that a S. cerevisiae strain overexpressing ScGRE3 and SsXYL2 had a lower growth rate and produced more xylitol than the strain overexpressing SsXYL1 and SsXYL2 (Toivari et al. Appl. Environ. Microbiol., 70: 3681-3686, (2004)). These results in the art suggest that overexpression of ScGRE3 is not recommended for constructing an efficient xylose-fermenting S. cerevisiae strain.